Key result
Off-label underdosing of rivaroxaban increased stroke or systemic embolism risk (HR 1.31; 95% CI 1.05-1.63), while apixaban underdosing increased all-cause death (HR 1.21; 95% CI 1.05-1.40).
Why the study?
Prior meta-analyses evaluating off-label underdosing versus recommended dosing of NOACs in AF combined different NOACs rather than evaluating each drug separately.
Does off-label underdosing of individual NOACs increase the risk of adverse outcomes compared to on-label dosing in patients with nonvalvular atrial fibrillation?
Meta-Analysis (n=144,797)
Does off-label underdosing of individual NOACs increase the risk of adverse outcomes compared to on-label dosing in patients with nonvalvular atrial fibrillation?
Hazard Ratio: 1.31 (95% CI 1.05–1.63)
p-value: p=0.02
Off-label underdosing of NOACs, specifically rivaroxaban and apixaban, is associated with increased risks of stroke/systemic embolism and all-cause death, respectively, highlighting the importance of adhering to guideline-recommended dosing in atrial fibrillation.
Individual NOAC underdosing effects vary by agent; challenges pooled prior analyses and leaves optimal dosing open.
BACKGROUND: Although several meta-analyses have examined the effects of off-label underdosing of nonvitamin K antagonist oral anticoagulants (NOACs) compared with their recommended doses in patients with atrial fibrillation (AF), they combined different kinds of NOACs in their primary analyses. Herein, we first conducted a meta-analysis to separately assess the effects of off-label underdosing versus on-label dosing of four individual NOACs on adverse outcomes in the AF population. METHODS: The PubMed and Embase database were systemically searched until November 2021 to identify the relevant studies. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by utilizing a random-effects model. RESULTS: A total of nine studies with 144,797 patients taking NOACs were included in the meta-analysis. In the pooled analysis, off-label underdosing of rivaroxaban was related to an increased risk of stroke or systemic embolism (HR = 1.31, 95% CI 1.05-1.63; p = .02), whereas off-label underdosing of apixaban was associated with a higher risk of all-cause death (HR = 1.21, 95% CI 1.05-1.40; p = .01). When comparing off-label underdosing versus on-label dosing of dabigatran or edoxaban, no differences were found in the primary and secondary clinical outcomes. CONCLUSION: Off-label underdosing of rivaroxaban may increase the risk of stroke or systematic embolism, whereas off-label underdosing of apixaban may heighten the incidence of all-cause death.
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Sang et al. (2022) conducted a meta-analysis in nonvalvular atrial fibrillation (n=144,797). Off-label underdosing of NOACs vs. On-label dosing of NOACs was evaluated on Stroke or systemic embolism (for rivaroxaban) (HR 1.31, 95% CI 1.05-1.63, p=0.02). Off-label underdosing of rivaroxaban increased stroke or systemic embolism risk (HR 1.31; 95% CI 1.05-1.63), while apixaban underdosing increased all-cause death (HR 1.21; 95% CI 1.05-1.40).
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